Tedman Austin, Goel Muskan, Shah Sohan, Schlebach Jonathan P
The James Tarpo Jr and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, Indiana, USA.
The James Tarpo Jr and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, Indiana, USA.
J Biol Chem. 2025 Jun 18;301(7):110375. doi: 10.1016/j.jbc.2025.110375.
Several diseases of protein misfolding can now be treated with an emerging class of therapeutics known as pharmacological chaperones, pharmacochaperones, or correctors. These small molecules exploit the universal thermodynamic coupling between ligand binding and protein folding to suppress conformational defects that disrupt protein homeostasis. While the mechanistic basis of their activity is quite simple in theory, their nuanced proteostatic effects can vary depending on the intrinsic properties of their target proteins and the cellular context. Deviations in activity are especially pronounced across panels of pathogenic variants of the target protein. In this perspective, we explore the factors that shape the potency of pharmacochaperones and the intrinsic sensitivity of different target proteins in relation to various theoretical considerations and experimental observations. We discuss how emerging technologies have provided general insights into the molecular basis of the variant-specific effects of certain pharmacochaperones. We also highlight ongoing efforts to identify existing drugs that stabilize misfolded variants and to repurpose them as pharmacochaperones. Finally, we discuss how the chaperone activity of current drugs could potentially contribute to complex pharmacology and deviations in therapeutic efficacy across patient cohorts. Together, these principles provide a coherent framework that may help guide the discovery and precision targeting of next-generation pharmacochaperones for both current and new targets involved in proteostasis diseases. An audio recording of this work is included in the supplement and can be freely streamed here.
现在，几种蛋白质错误折叠疾病可以用一类新兴的治疗药物来治疗，这类药物被称为药理伴侣、药物伴侣或校正剂。这些小分子利用配体结合与蛋白质折叠之间普遍存在的热力学偶联，来抑制破坏蛋白质稳态的构象缺陷。虽然它们的作用机制在理论上相当简单，但其细微的蛋白质稳态效应可能会因靶蛋白的内在特性和细胞环境而异。在靶蛋白的致病性变体组中，活性偏差尤为明显。从这个角度出发，我们探讨了影响药物伴侣效力的因素，以及不同靶蛋白相对于各种理论考量和实验观察的内在敏感性。我们讨论了新兴技术如何为某些药物伴侣的变体特异性效应的分子基础提供了一般性见解。我们还强调了目前为鉴定能稳定错误折叠变体的现有药物并将其重新用作药物伴侣所做的努力。最后，我们讨论了当前药物的伴侣活性如何可能导致复杂的药理学以及不同患者群体之间治疗效果的偏差。总之，这些原则提供了一个连贯的框架，可能有助于指导针对蛋白质稳态疾病中现有和新靶点的下一代药物伴侣的发现和精准靶向。这项工作的音频记录包含在补充材料中，可在此处免费收听。
